Features | Partner Sites | Information | LinkXpress
Sign In
JIB
GLOBETECH PUBLISHING
BioConferenceLive

Dislocated Enzyme Causes Hereditary Lysosomal Storage Disease

By BiotechDaily International staff writers
Posted on 03 Mar 2014
Image: In normal cells, phosphotransferase (green) is shown overlapping with the Golgi apparatus (red), which indicates that phosphotransferase is located in the Golgi, where it should be (Photo courtesy of Dr. Eline van Meel, Washington University School of Medicine).
Image: In normal cells, phosphotransferase (green) is shown overlapping with the Golgi apparatus (red), which indicates that phosphotransferase is located in the Golgi, where it should be (Photo courtesy of Dr. Eline van Meel, Washington University School of Medicine).
Image: In mutant cells, the protein phosphotransferase (green) is spread beyond the Golgi (red). Outside the Golgi, this wayward phosphotransferase is no longer able to perform its job of properly addressing enzymes bound for the lysosome (Photo courtesy of Dr. Eline van Meel, Washington University School of Medicine).
Image: In mutant cells, the protein phosphotransferase (green) is spread beyond the Golgi (red). Outside the Golgi, this wayward phosphotransferase is no longer able to perform its job of properly addressing enzymes bound for the lysosome (Photo courtesy of Dr. Eline van Meel, Washington University School of Medicine).
The molecular mechanism that underlies the hereditary lysosomal disorder mucolipidosis III has been traced to a mutation that causes a specific enzyme to leach out of the Golgi apparatus and into the cell where it is degraded by the lysosome or released into the medium.

Mucolipidosis III results from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase, which phosphorylates target carbohydrate residues on N-linked glycoproteins. Without this phosphorylation, the glycoproteins are not shipped to the lysosomes, and they escape outside the cell. This rare disorder is characterized by skeletal and heart abnormalities, which can result in a shortened lifespan.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) reported in the February 18, 2014, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that the Golgi-localized enzyme normally mediates the first step in the synthesis of the mannose 6-phosphate recognition marker on lysosomal acid hydrolases, and loss of this function results in impaired lysosomal targeting of these acid hydrolases and decreased lysosomal degradation.

They described two missense mutations in the N-terminal cytoplasmic tail of the alpha subunit of the phosphotransferase that impair retention of the catalytically active enzyme in the Golgi complex. This results in mistargeting of the mutant phosphotransferases to lysosomes, where they are degraded, or to the cell surface and release into the medium. As a result, children with this disorder have lysosomal proteins in their blood at levels 10 to 20 times higher than normal.

“Type III patients live into adulthood, but they are very impaired,” said senior author Dr. Stuart A. Kornfeld, professor of medicine at Washington University School of Medicine. “They have joint and heart problems and have trouble walking. In the most severe form, type II, there is zero activity of phosphotransferase. None of the 60 enzymes are properly tagged, so these patients’ lysosomes are empty. Children with type II usually die by age 10.”

“Under normal circumstances, the phosphotransferase moves up through the Golgi, but then it is recaptured and sent back,” said Dr. Kornfeld. “Our study shows that the mutant phosphotransferase moves up but is not recaptured. Ironically, the phosphotransferase that escapes the Golgi ends up in the lysosomes, where it is degraded. There is a lot of interest and study about how cells distribute proteins to the right parts of the cell. Our study has identified one of the few examples of a genetic disease caused by the misplacement of a protein. The protein functions just fine. It just does not stay in the right place. We think there must be some protein in the cell that recognizes phosphotransferase when it gets to the end of the Golgi, binds it and takes it back. Now we are trying to understand how that works.”

Related Links:

Washington University School of Medicine



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: Molecular rendering of the crystal structure of parkin (Photo courtesy of Wikimedia Commons).

Cinnamon Feeding Blocks Development of Parkinson's Disease in Mouse Model

A team of neurological researchers has identified a molecular mechanism by which cinnamon acts to protect neurons from damage caused by Parkinson's disease (PD) in a mouse model of the syndrome.... Read more

Therapeutics

view channel
Image: This type of electronic pacemaker could become obsolete if induction of biological pacemaker cells by gene therapy proves successful (Photo courtesy of Wikimedia Commons).

Gene Therapy Induces Functional Pacemaker Cells in Pig Heart Failure Model

Cardiovascular disease researchers working with a porcine heart failure model have demonstrated the practicality of using gene therapy to replace implanted electronic pacemakers to regulate heartbeat.... Read more

Lab Technologies

view channel

Precise Ion Irradiation Dosing Method Developed for Cancer Therapy

Scientists are employing nuclear physics principles to provide more effective approaches to radiotherapy treatment for cancer patients. Radiation therapy using heavy ions is best suitable for cancer patients with tumors that are difficult to access, such as in the brain. These particles scarcely damage the penetrated... Read more

Business

view channel

Cancer Immunotherapy Sector Predicted to Surge to USD 9 Billion Across Major Pharma Through 2022

The immunotherapy market will experience substantial growth through 2022, increasing from USD 1.1 billion in 2012 to nearly USD 9 billion in 2022 (corresponding to 23.8% annual growth) in the United Kingdom, United States, France, Germany, Italy, Spain, and Japan, according to recent market research. This notable growth... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.